Immunotherapy in Melanoma, Gastrointestinal (GI), and Pulmonary Malignancies

  • Received: 21 February 2015 Accepted: 20 March 2015 Published: 25 January 2015
  • Oncologic immunotherapy involves stimulating the immune system to more effectively identify and eradicate tumor cells that have successfully adapted to survive the body's natural immune defenses. Immunotherapy has shown great promise thus far by prolonging the lives of patients with a variety of malignancies, and has added a crucial new set of tools to the oncologists' armamentarium. The aim of this paper is to provide an overview of immunotherapy treatment options that are currently available and under active research for melanoma, gastrointestinal (esophageal, gastric, pancreatic, and colorectal), and pulmonary malignancies. Potential biomarkers that may predict favorable responses to immunotherapies are discussed where applicable, as are future avenues of research in this rapidly evolving field.

    Citation: Alexander B. Dillon, Kevin Lin, Andrew Kwong, Susana Ortiz. Immunotherapy in Melanoma, Gastrointestinal (GI), and Pulmonary Malignancies[J]. AIMS Public Health, 2015, 2(1): 86-114. doi: 10.3934/publichealth.2015.1.86

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  • Oncologic immunotherapy involves stimulating the immune system to more effectively identify and eradicate tumor cells that have successfully adapted to survive the body's natural immune defenses. Immunotherapy has shown great promise thus far by prolonging the lives of patients with a variety of malignancies, and has added a crucial new set of tools to the oncologists' armamentarium. The aim of this paper is to provide an overview of immunotherapy treatment options that are currently available and under active research for melanoma, gastrointestinal (esophageal, gastric, pancreatic, and colorectal), and pulmonary malignancies. Potential biomarkers that may predict favorable responses to immunotherapies are discussed where applicable, as are future avenues of research in this rapidly evolving field.

    [1] Coley WB (1893) The Treatment of Malignant Tumors by Repeated Innoculations of Erysipelas: With a Report of Ten Original Cases. Am J Med Sci 10: 487-511.
    [2] Pick TP (1899) Surgery: Green. 1208 p.
    [3] Menzies SW, McCarthy WH (1997) Complete regression of primary cutaneous malignant melanoma. Arch Surg 132: 553-556. doi: 10.1001/archsurg.1997.01430290099020
    [4] Quaglino P, Marenco F, Osella-Abate S, et al. (2010) Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study. Ann Onc 21: 409-414. doi: 10.1093/annonc/mdp325
    [5] Topalian SL, Sznol M, McDermott DF, et al. (2014) Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab. J Clin Onc 32:1020-1030. doi: 10.1200/JCO.2013.53.0105
    [6] Rosenberg SA, Yang JC, Sherry RM, et al. (2011) Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy. Clin Cancer Res 17: 4550-4557. doi: 10.1158/1078-0432.CCR-11-0116
    [7] McDermott D, Lebbé|C, Hodi FS, et al. (2014) Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat Rev 40: 1056-1064. doi: 10.1016/j.ctrv.2014.06.012
    [8] Sanlorenzo M, Vujic I, Posch C, et al. (2014) Melanoma immunotherapy. Cancer Biol Ther 15:665-674. doi: 10.4161/cbt.28555
    [9] Avril MF, Aamdal S, Grob JJ, et al. (2004) Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Onc.22: 1118-1125.
    [10] Garbe C, Eigentler TK, Keilholz U, et al. (2011) Systematic Review of Medical Treatment in Melanoma: Current Status and Future Prospects. Oncologist 16: 5-24. doi: 10.1634/theoncologist.2010-0190
    [11] Hervas-Stubbs S, Perez-Gracia JL, Rouzaut A, et al. (2011) Direct effects of type I interferons on cells of the immune system. Clin Cancer Res 17: 2619-2627. doi: 10.1158/1078-0432.CCR-10-1114
    [12] Kirkwood JM, Strawderman MH, Ernstoff MS, et al. (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST1684. J Clin Onc 14: 7-17.
    [13] Payne MJ, Argyropoulou K, Lorigan P, et al. (2014) Phase II Pilot Study of Intravenous High-Dose Interferon With or Without Maintenance Treatment in Melanoma at High Risk of Recurrence. J Clin Onc 32: 185-190. doi: 10.1200/JCO.2013.49.8717
    [14] Di Trolio R, Simeone E, Di Lorenzo G, et al. (2014) The use of interferon in melanoma patients: A systematic review. Cytokine Growth Factor Rev Epub
    [15] Kaufman HL, Kirkwood JM, Hodi FS, et al. (2013) The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. Nat Rev Clin Onc 10: 588-598. doi: 10.1038/nrclinonc.2013.153
    [16] Baker DE (2001) Pegylated interferons. Rev Gastroenterol Disord 1: 87-99.
    [17] Eggermont AMM, Suciu S, Testori A, et al. (2012) Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 48: 218-225. doi: 10.1016/j.ejca.2011.09.028
    [18] Hofmann MA, Kiecker F, Küchler I, et al. (2011) Serum TNF-α, B2M and sIL-2R levels are biological correlates of outcome in adjuvant IFN-α2b treatment of patients with melanoma. J Cancer Res Clin Onc 137: 455-462. doi: 10.1007/s00432-010-0900-1
    [19] Flaherty LE, Othus M, Atkins MB, et al. (2014) Southwest Oncology Group S0008: A Phase III Trial of High-Dose Interferon Alfa-2b Versus Cisplatin, Vinblastine, and Dacarbazine, Plus Interleukin-2 and Interferon in Patients With High-Risk Melanoma-An Intergroup Study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Onc 32: 3771-3778. doi: 10.1200/JCO.2013.53.1590
    [20] Kim KB, Legha SS, Gonzalez R, et al. (2009) A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence. Melanoma Res 19: 42-49. doi: 10.1097/CMR.0b013e328314b84a
    [21] Atkins MB, Kunkel L, Sznol M, et al. (2000) High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sc Am 6: S11-14.
    [22] Schwartzentruber DJ (2001) Guidelines for the safe administration of high-dose interleukin-2. J Immunotherapy (Hagerstown, Md: 1997) 24: 287-293. doi: 10.1097/00002371-200107000-00004
    [23] Petrella T, Quirt I, Verma S, et al. (2007) Single-agent interleukin-2 in the treatment of metastatic melanoma: A systematic review. Cancer Treat Rev 33: 484-496. doi: 10.1016/j.ctrv.2007.04.003
    [24] Joseph RW, Sullivan RJ, Harrell R, et al. (2012) Correlation of NRAS Mutations With Clinical Response to High-dose IL-2 in Patients With Advanced Melanoma. J Immunotherapy 35: 66-72. doi: 10.1097/CJI.0b013e3182372636
    [25] Keilholz U, Conradt C, Legha SS, et al. (1998) Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Onc 16: 2921-2929.
    [26] Byers BA, Temple-Oberle CF, Hurdle V, et al. (2014) Treatment of in-transit melanoma with intra-lesional interleukin-2: A systematic review. J Surg Onc 110: 770-775. doi: 10.1002/jso.23702
    [27] Boyd KU, Wehrli BM, Temple CLF (2011) Intra-lesional interleukin-2 for the treatment of in-transit melanoma. J Surg Onc 104: 711-717. doi: 10.1002/jso.21968
    [28] Daud AI, DeConti RC, Andrews S, et al. (2008) Phase I trial of interleukin-12 plasmid electroporation in patients with metastatic melanoma. J Clin Onc 26: 5896-5903.
    [29] Dillman RO, Cornforth AN, Depriest C, et al. (2012) Tumor stem cell antigens as consolidative active specific immunotherapy: a randomized phase II trial of dendritic cells versus tumor cells in patients with metastatic melanoma. J Immunotherapy 35: 641-649. doi: 10.1097/CJI.0b013e31826f79c8
    [30] Dillman RO, DePriest C, Ellis RA (2014) Long-term survival for patients with detectable metastatic melanoma at time of treatment with patient-specific tumor stem cell vaccines. J Clin Onc 32: 5s. doi: 10.1200/JCO.2013.49.4757
    [31] Dudley ME, Yang JC, Sherry R, et al. (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Onc 26: 5233-5239. doi: 10.1200/JCO.2008.16.5449
    [32] Radvanyi LG, Bernatchez C, Zhang M, et al. (2012) Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients. Clin Cancer Res 18: 6758-6770. doi: 10.1158/1078-0432.CCR-12-1177
    [33] Besser MJ, Shapira-Frommer R, Treves AJ, et al. (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16: 2646-2655. doi: 10.1158/1078-0432.CCR-10-0041
    [34] Collins AV, Brodie DW, Gilbert RJC, et al. (2002) The interaction properties of costimulatory molecules revisited. Immunity 17: 201-210. doi: 10.1016/S1074-7613(02)00362-X
    [35] Hodi FS, O'Day SJ, McDermott DF, et al. (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363: 711-723. doi: 10.1056/NEJMoa1003466
    [36] Wolchok JD, Neyns B, Linette G, et al. (2010) Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Onc 11: 155-164. doi: 10.1016/S1470-2045(09)70334-1
    [37] Robert C, Thomas L, Bondarenko I, et al. (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517-2526. doi: 10.1056/NEJMoa1104621
    [38] Lebbé|C, Weber JS, Maio M, et al. (2014) Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann Onc/ESMO 25: 2277-2284. doi: 10.1093/annonc/mdu441
    [39] Schadendorf D, FS Hodi, C Robert, et al. (2013) Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. ESMO 2013 Congress.
    [40] Chiarion-Sileni V, Pigozzo J, Ascierto PA, et al. (2014) Ipilimumab retreatment in patients with pretreated advanced melanoma: the expanded access programme in Italy. Br J Cancer 110:1721-1726. doi: 10.1038/bjc.2014.126
    [41] Dequen P, Lorigan P, Jansen JP, et al. (2012) Systematic review and network meta-analysis of overall survival comparing 3 mg/kg ipilimumab with alternative therapies in the management of pretreated patients with unresectable stage III or IV melanoma. Oncologist 17: 1376-1385. doi: 10.1634/theoncologist.2011-0427
    [42] Ascierto PA, Simeone E, Sileni VC, et al. (2014) Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. Cancer Inves. 32: 144-149. doi: 10.3109/07357907.2014.885984
    [43] Hodi FS, Lee S, McDermott DF, et al. (2014) Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial. JAMA 312: 1744-1753. doi: 10.1001/jama.2014.13943
    [44] Bapodra A, Silva IEDPD, Lui KP, et al. (2014) Clinical outcome and CD4+ differentiation in anti-CTLA-4/radiation and anti-CTLA-4/steroid therapy. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [45] Downey SG, Klapper JA, Smith FO, et al. (2007) Prognostic factors related to clinical response in patients with metastatic melanoma treated by CTL-associated antigen-4 blockade. Clin Cancer Res 13: 6681-6688. doi: 10.1158/1078-0432.CCR-07-0187
    [46] Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. (2014) Ipilimumab versus placebo after complete resection of stage III melanoma: Initial efficacy and safety results from the EORTC 18071 phase III trial. J Clin Onc 32: 5s. doi: 10.1200/JCO.2013.49.4757
    [47] Hamid O, Schmidt H, Nissan A, et al. (2011) A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma. J Transl Med 9: 204. doi: 10.1186/1479-5876-9-204
    [48] Adaniel C, Rendleman J, Polsky D, et al. (2014) Germline genetic determinants of immunotherapy response in metastatic melanoma. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [49] Freeman-Keller M, Weber JS (2015) Anti-programmed death receptor 1 immunotherapy in melanoma: rationale, evidence and clinical potential. Ther Adv Med Onc 7: 12-21. doi: 10.1177/1758834014551747
    [50] Weber JS, Minor DR, D'Angelo S, et al. (2014) A Phase 3 randomized, open-label study of nivolumab (anti-PD-1|BMS-936558|ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. ESMO 2014 Congress.
    [51] Hamid O, Robert C, Daud A, et al. (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369: 134-144. doi: 10.1056/NEJMoa1305133
    [52] Robert C, Ribas A, Wolchok JD, et al. (2014) Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. The Lancet 384: 1109-1117. doi: 10.1016/S0140-6736(14)60958-2
    [53] Robert C, Joshua AM, Weber AS (2014) Pembrolizumab (pembro|MK-3475) for advanced melanoma (MEL): Randomized comparison of two dosing schedules. ESMO 2014 Congress.
    [54] Ribas A, Hodi FS, Kefford R, et al. (2014) Efficacy and safety of the anti-PD-1 monoclonal antibody MK-3475 in 411 patients (pts) with melanoma (MEL). J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [55] Kefford R, Ribas A, Hamid O, et al. (2014) Clinical efficacy and correlation with tumor PD-L1 expression in patients (pts) with melanoma (MEL) treated with the anti-PD-1 monoclonal antibody MK-3475. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [56] Wolchok JD, Kluger H, Callahan MK, et al. (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369: 122-133. doi: 10.1056/NEJMoa1302369
    [57] Sharabi AB, Nirschl CJ, Kochel CM, et al. (2014) Stereotactic Radiation Therapy Augments Antigen-Specific PD-1 Mediated Anti-Tumor Immune Responses via Cross-Presentation of Tumor Antigen. Cancer Immunol Res.: canimm.0196.2014.
    [58] Brahmer JR, Tykodi SS, Chow LQM, et al. (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366: 2455-2465. doi: 10.1056/NEJMoa1200694
    [59] Fonsatti E, Maio M, Altomonte M, et al. (2010) Biology and Clinical Applications of CD40 in Cancer Treatment. Seminars Onc 37: 517-523. doi: 10.1053/j.seminoncol.2010.09.002
    [60] Vonderheide RH, Flaherty KT, Khalil M, et al. (2007) Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Onc 25: 876-883. doi: 10.1200/JCO.2006.08.3311
    [61] Hemon P, Jean-Louis F, Ramgolam K, et al. (2011) MHC class II engagement by its ligand LAG-3 (CD223) contributes to melanoma resistance to apoptosis. J Immunol 186: 5173-5183. doi: 10.4049/jimmunol.1002050
    [62] Baitsch L, Baumgaertner P, Devêvre E, et al. (2011) Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients. J Clin Invest 121: 2350-2360. doi: 10.1172/JCI46102
    [63] da Silva IP, Gallois A, Jimenez-Baranda S, et al. (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2: 410-422. doi: 10.1158/2326-6066.CIR-13-0171
    [64] Lombardi VC, Khaiboullina SF, Rizvanov AA (2015) Plasmacytoid dendritic cells, a role in neoplastic prevention and progression. Eur J Clin Invest 45: 1-8.
    [65] Aspord C, Tramcourt L, Leloup C, et al. (2014) Imiquimod inhibits melanoma development by promoting pDC cytotoxic functions and impeding tumor vascularization. J Invest Derm 134:2551-2561. doi: 10.1038/jid.2014.194
    [66] Hyde MA, Hadley ML, Tristani-Firouzi P, et al. (2012) A randomized trial of the off-label use of imiquimod, 5%, cream with vs without tazarotene, 0.1%, gel for the treatment of lentigo maligna, followed by conservative staged excisions. Arch Derm 148: 592-596.
    [67] Singh M, Khong H, Dai Z, et al. (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193: 4722-4731. doi: 10.4049/jimmunol.1401160
    [68] Andtbacka RHI, Collichio FA, Amatruda T, et al. (2013) OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. J Clin Onc 31.
    [69] Andtbacka RHI, Curti BD, Kaufman H, et al. (2014) CALM study: A phase II study of an intratumorally delivered oncolytic immunotherapeutic agent, coxsackievirus A21, in patients with stage IIIc and stage IV malignant melanoma. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [70] Zamarin D, Holmgaard RB, Subudhi SK, et al. (2014) Potentiation of immune checkpoint blockade cancer immunotherapy with oncolytic virus. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [71] Schipper H, Alla V, Meier C, et al. (2014) Eradication of metastatic melanoma through cooperative expression of RNA-based HDAC1 inhibitor and p73 by oncolytic adenovirus. Oncotarget 5: 5893-5907.
    [72] Jemal A, Bray F, Center MM, et al. (2011) Global cancer statistics. CA Cancer J Clin 61: 69-90. doi: 10.3322/caac.20107
    [73] 74. Kono K, Mizukami Y, Daigo Y, et al. (2009) Vaccination with multiple peptides derived from novel cancer-testis antigens can induce specific T-cell responses and clinical responses in advanced esophageal cancer. Cancer Sci 100: 1502-1509. doi: 10.1111/j.1349-7006.2009.01200.x
    [74] 75. Iinuma H, Fukushima R, Inaba T, et al. (2014) Phase I clinical study of multiple epitope peptide vaccine combined with chemoradiation therapy in esophageal cancer patients. J Transl Med 12:84. doi: 10.1186/1479-5876-12-84
    [75] 76. Toh U, Yamana H, Sueyoshi S, et al. (2000) Locoregional cellular immunotherapy for patients with advanced esophageal cancer. Clin Cancer Res 6: 4663-4673.
    [76] 77. Akutsu Y, Qin W, Murakami K, et al. (2014) The effect of stress on efficacy of dendritic cell therapy for esophageal squamous cell carcinoma. J Clin Onc32.
    [77] 79. Crew KD, Neugut AI (2006) Epidemiology of gastric cancer. World J Gastroenterol 12:354-362.
    [78] 80. Ohtsu A, Shah MA, Van Cutsem E, et al. (2011) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Onc 29: 3968-3976. doi: 10.1200/JCO.2011.36.2236
    [79] 81. Bang Y-J, Van Cutsem E, Feyereislova A, et al. (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376: 687-697. doi: 10.1016/S0140-6736(10)61121-X
    [80] 82. Ajani JA, Hecht JR, Ho L, et al. (2006) An open-label, multinational, multicenter study of G17DT vaccination combined with cisplatin and 5-fluorouracil in patients with untreated,advanced gastric or gastroesophageal cancer: the GC4 study. Cancer 106: 1908-1916. doi: 10.1002/cncr.21814
    [81] 83. Masuzawa T, Fujiwara Y, Okada K, et al. (2012) Phase I/II study of S-1 plus cisplatin combined with peptide vaccines for human vascular endothelial growth factor receptor 1 and 2 in patients with advanced gastric cancer. Int J Onc 41: 1297-1304.
    [82] 84. Popiela T, Kulig J, Czupryna A, et al. (2004) Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer. Gastric Cancer 7:240-245. doi: 10.1007/s10120-004-0299-y
    [83] 85. Kono K, Takahashi A, Sugai H, et al. (2002) Dendritic cells pulsed with HER-2/neu-derived peptides can induce specific T-cell responses in patients with gastric cancer. Clin Cancer Res 8:3394-3400.
    [84] 86. Kono K, Takahashi A, Ichihara F, et al. (2002) Prognostic significance of adoptive immunotherapy with tumor-associated lymphocytes in patients with advanced gastric cancer: a randomized trial. Clin Cancer Res 8: 1767-1771.
    [85] 87. Jiang J-T, Shen Y-P, Wu C-P, et al. (2010) Increasing the frequency of CIK cells adoptive immunotherapy may decrease risk of death in gastric cancer patients. World J Gastroenterol 16:6155-6162. doi: 10.3748/wjg.v16.i48.6155
    [86] 88. Shi L, Zhou Q, Wu J, et al. (2012) Efficacy of adjuvant immunotherapy with cytokine-induced killer cells in patients with locally advanced gastric cancer. Cancer Immunol. Immunotherapy 61:2251-2259. doi: 10.1007/s00262-012-1289-2
    [87] 89. Jeung H-C, Moon YW, Rha SY, et al. (2008) Phase III trial of adjuvant 5-fluorouracil and adriamycin versus 5-fluorouracil, adriamycin, and polyadenylic-polyuridylic acid (poly A:U) for locally advanced gastric cancer after curative surgery: final results of 15-year follow-up. Ann Onc/ESMO 19: 520-526.
    [88] 90. Muro K, Bang Y, Shankaran V, et al. (2014) A phase 1b study of pembrolizumab (Pembro|MK-3475) in patients (Pts) with advanced gastric cancer. ESMO 2014 Congress.
    [89] 91. Diermeier-Daucher S, Ortmann O, Buchholz S, et al. (2012) Trifunctional antibody ertumaxomab. mAbs 4: 614-622. doi: 10.4161/mabs.21003
    [90] 92. Haense N, Pauligk C, Marme F, et al. (2014) Interim analysis of a phase I/II open label, dose-escalating study to investigate safety, tolerability, and preliminary efficacy of the trifunctional anti-HER2/neu x anti-CD3 antibody ertumaxomab in patients with HER2/neu expressing solid tumors progressing after standard therapy. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [91] 93. Atanackovic D, Reinhard H, Meyer S, et al. (2013) The trifunctional antibody catumaxomab amplifies and shapes tumor-specific immunity when applied to gastric cancer patients in the adjuvant setting. Hum Vaccines Immunotherapeutics 9: 2533-2542. doi: 10.4161/hv.26065
    [92] 94. Heiss MM, Murawa P, Koralewski P, et al. (2010) The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial. Int J Cancer 127: 2209-2221. doi: 10.1002/ijc.25423
    [93] 95. Matsueda S (2014) Immunotherapy in gastric cancer. World J Gastroenterol 20: 1657. doi: 10.3748/wjg.v20.i7.1657
    [94] 96. Gabitass RF, Annels NE, Stocken DD, et al. (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13. Cancer Immunol Immunother 60: 1419-1430. doi: 10.1007/s00262-011-1028-0
    [95] 97. Mundy-Bosse BL, Young GS, Bauer T, et al. (2011) Distinct myeloid suppressor cell subsets correlate with plasma IL-6 and IL-10 and reduced interferon-alpha signaling in CD4+ T cells from patients with GI malignancy. Cancer Immunol Immunother: CII 60: 1269-1279. doi: 10.1007/s00262-011-1029-z
    [96] 98. Jaffee E (2014) Cancer Research Institute: Pancreatic Cancer. Available from:
    [97] 99. Toomey PG, Vohra NA, Ghansah T, et al. (2013) Immunotherapy for gastrointestinal malignancies. Cancer Control 20: 32-42.
    [98] 100. Uram JN, Le DT (2013) Current advances in immunotherapy for pancreatic cancer. Curr. Problems Cancer 37: 273-279. doi: 10.1016/j.currproblcancer.2013.10.004
    [99] 101. Lepisto AJ, Moser AJ, Zeh H, et al. (2008) A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 6: 955-964.
    [100] 102. Bernhardt SL, Gjertsen MK, Trachsel S, et al. (2006) Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study. Br J Cancer 95:1474-1482. doi: 10.1038/sj.bjc.6603437
    [101] 103. Salman B, Zhou D, Jaffee EM, et al. (2013) Vaccine therapy for pancreatic cancer. Oncoimmunology 2: e26662. doi: 10.4161/onci.26662
    [102] 104. Middleton GW, Valle JW, Wadsley J, et al. (2013) A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. J Clin Onc 31.
    [103] 105. Asahara S, Takeda K, Yamao K, et al. (2013) Phase I/II clinical trial using HLA-A24-restricted peptide vaccine derived from KIF20A for patients with advanced pancreatic cancer. J Transl Med 11: 291. doi: 10.1186/1479-5876-11-291
    [104] 106. Gjertsen MK, Buanes T, Rosseland AR, et al. (2001) Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int J Cancer 92: 441-450. doi: 10.1002/ijc.1205
    [105] 107. Wedén S, Klemp M, Gladhaug IP, et al. (2011) Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int J Cancer 128: 1120-1128. doi: 10.1002/ijc.25449
    [106] 108. Jaffee EM, Hruban RH, Biedrzycki B, et al. (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Onc 19: 145-156.
    [107] 109. Lutz E, Yeo CJ, Lillemoe KD, et al. (2011) A Lethally Irradiated Allogeneic Granulocyte-Macrophage Colony Stimulating Factor-Secreting Tumor Vaccine for Pancreatic Adenocarcinoma: A Phase II Trial of Safety, Efficacy, and Immune Activation. Ann Surg 253:328-335. doi: 10.1097/SLA.0b013e3181fd271c
    [108] 110. Le DT, Wang-Gillam A, Picozzi V, et al. (2014) A phase 2, randomized trial of GVAX pancreas and CRS-207 immunotherapy versus GVAX alone in patients with metastatic pancreatic adenocarcinoma: Updated results. J Clin Onc 32.
    [109] 111. Rossi GR, Lima CMSR, Hardacre JM, et al. (2014) Correlation of anti-calreticulin antibody titers with improved overall survival in a phase 2 clinical trial of algenpantucel-L immunotherapy for patients with resected pancreatic cancer. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [110] 112. Starodub A, Ocean AJ, Messersmith WA, et al. (2015) Phase I/II trial of IMMU-132 (isactuzumab govitecan), an anti-Trop-2-SN-38 antibody drug conjugate (ADC): Results in patients with metastatic gastrointestinal (GI) cancers. J Clin Onc 33.
    [111] 113. Kondo H, Hazama S, Kawaoka T, et al. (2008) Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res 28:379-387.
    [112] 114. Chung MJ, Park JY, Bang S, et al. (2014) Phase II clinical trial of ex vivo-expanded cytokine-induced killer cells therapy in advanced pancreatic cancer. Cancer Immunol Immunother 63: 939-946. doi: 10.1007/s00262-014-1566-3
    [113] 115. Royal RE, Levy C, Turner K, et al. (2010) Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunotherapy (Hagerstown, Md: 1997) 33: 828-833. doi: 10.1097/CJI.0b013e3181eec14c
    [114] 116. Le DT, Lutz E, Uram JN, et al. (2013) Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J Immunotherapy (Hagerstown, Md: 1997) 36: 382-389.
    [115] 117. Beatty GL, Chiorean EG, Fishman MP, et al. (2011) CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331: 1612-1616. doi: 10.1126/science.1198443
    [116] 118. Pernot S, Terme M, Voron T, et al. (2014) Colorectal cancer and immunity: what we know and perspectives. World J Gastroenterol 20: 3738-3750. doi: 10.3748/wjg.v20.i14.3738
    [117] 120. Staff C, Mozaffari F, Haller BK, et al. (2011) A Phase I safety study of plasmid DNA immunization targeting carcinoembryonic antigen in colorectal cancer patients. Vaccine 29:6817-6822. doi: 10.1016/j.vaccine.2010.12.063
    [118] 121. Albanopoulos K, Armakolas A, Konstadoulakis MM, et al. (2000) Prognostic significance of circulating antibodies against carcinoembryonic antigen (anti-CEA) in patients with colon cancer. Am J Gastroenterol 95: 1056-1061. doi: 10.1111/j.1572-0241.2000.01982.x
    [119] 122. Conry RM, Allen KO, Lee S, et al. (2000) Human autoantibodies to carcinoembryonic antigen (CEA) induced by a vaccinia-CEA vaccine. Clin Cancer Res 6: 34-41.
    [120] 123. Loibner H, Eckert H, Eller N (2004) A randomized placebo-controlled phase II study with the cancer vaccine IGN101 in patients with epithelial solid organ tumors (IGN101/2-01). J Clin Oncol 22: 2619.
    [121] 124. Karanikas V, Thynne G, Mitchell P, et al. (2001) Mannan Mucin-1 Peptide Immunization: Influence of Cyclophosphamide and the Route of Injection. J Immunotherapy 24: 172-183. doi: 10.1097/00002371-200103000-00012
    [122] 125. Hazama S, Nakamura Y, Takenouchi H, et al. (2014) A phase I study of combination vaccine treatment of five therapeutic epitope-peptides for metastatic colorectal cancer|safety, immunological response, and clinical outcome. J Transl Med 12: 63.
    [123] 126. Ibrahim R, Achtar M, Herrin V (2004) Mutant P53 vaccination of patients with advanced cancers generates specific immunological responses. J Clin Oncol 22: 2521.
    [124] 127. Toubaji A, Achtar M, Provenzano M, et al. (2008) Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol Immunother 57: 1413-1420. doi: 10.1007/s00262-008-0477-6
    [125] 128. Harris JE, Ryan L, Hoover HC, et al. (2000) Adjuvant active specific immunotherapy for stage II and III colon cancer with an autologous tumor cell vaccine: Eastern Cooperative Oncology Group Study E5283. J Clin Onc 18: 148-157.
    [126] 129. Uyl-de Groot CA, Vermorken JB, Hanna MG, et al. (2005) Immunotherapy with autologous tumor cell-BCG vaccine in patients with colon cancer: a prospective study of medical and economic benefits. Vaccine 23: 2379-2387. doi: 10.1016/j.vaccine.2005.01.015
    [127] 130. Schulze T, Kemmner W, Weitz J, et al. (2009) Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother 58: 61-69. doi: 10.1007/s00262-008-0526-1
    [128] 131. Parkhurst MR, Yang JC, Langan RC, et al. (2011) T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther 19: 620-626. doi: 10.1038/mt.2010.272
    [129] 132. Chung KY, Gore I, Fong L, et al. (2010) Phase II study of the anti-cytotoxic T-lymphocyte-associated antigen 4 monoclonal antibody, tremelimumab, in patients with refractory metastatic colorectal cancer. J Clin Onc 28: 3485-3490. doi: 10.1200/JCO.2010.28.3994
    [130] 133. Brahmer JR, Drake CG, Wollner I, et al. (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Onc 28: 3167-3175. doi: 10.1200/JCO.2009.26.7609
    [131] 134. Lipson EJ, Sharfman WH, Drake CG, et al. (2013) Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res 19: 462-468. doi: 10.1158/1078-0432.CCR-12-2625
    [132] 135. Dela Cruz CS, Tanoue LT, Matthay RA (2011) Lung Cancer: Epidemiology, Etiology, and Prevention. Clin Chest Med 32.
    [133] 136. Quoix E, Sequist L, Nemunaitis J, et al. (2014) TG4010 immunotherapy combined with first-line therapy in advanced non-small cell lung cancer (NSCLC): phase IIb results of the TIME study. J Immunother Cancer 2: O12. doi: 10.1186/2051-1426-2-S3-O12
    [134] 137. Lynch TJ, Bondarenko I, Luft A, et al. (2012) Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Onc 30: 2046-2054. doi: 10.1200/JCO.2011.38.4032
    [135] 138. Brahmer JR, Horn L, Gandhi L, et al. (2014) Nivolumab (anti-PD-1, BMS-936558, ONO-4538) in patients (pts) with advanced non-small-cell lung cancer (NSCLC): Survival and clinical activity by subgroup analysis. J Clin Onc 32: 5s. doi: 10.1200/JCO.2013.49.4757
    [136] 139. Topalian SL, Hodi FS, Brahmer JR, et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366: 2443-2454. doi: 10.1056/NEJMoa1200690
    [137] 140. Garon EB, Gandhi L, Rizvi N, et al. (2014) Lba43antitumor Activity of Pembrolizumab (pembro|Mk-3475) and Correlation with Programmed Death Ligand 1 (pd-L1) Expression in a Pooled Analysis of Patients (pts) with Advanced Non–Small Cell Lung Carcinoma (nsclc). Ann Onc 25: mdu438.
    [138] 141. Johnson DB, Rioth MJ, Horn L (2014) Immune Checkpoint Inhibitors in NSCLC. Curr Treat Options Onc 15: 658-669. doi: 10.1007/s11864-014-0305-5
    [139] 142. Spigel DR, Gettinger SN, Horn L, et al. (2013) Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Onc 31.
    [140] 143. Brahmer JR, Rizvi NA, Lutzky J, et al. (2014) Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Onc 32:5s. doi: 10.1200/JCO.2013.49.4757
    [141] 144. Antonia SJ, Gettinger SN, Chow LQM, et al. (2014) Nivolumab (anti-PD-1|BMS-936558, ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. J Clin Onc 32:5s.
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